【作者】 康祖铭；

【导师】 凌天牖；

【作者基本信息】 中南大学 ， 内科学， 2011， 博士

【摘要】 目的分析一个中国土家族下颌前突家系的临床和遗传学特征,并检测其基因突变情况,为研究下颌前突的遗传学发病机制打下基础。方法收集下颌前突家系,设计调查表,调查家系家族史等资料,对家系成员进行全身检查和口腔专科检查,拍摄侧位相片和头颅定位侧位X线片,分析家系的临床资料,总结其临床特征；同时,整理家族史资料,绘制家系系谱图,分析其遗传特征。在知情同意的前提下,抽取先证者和部分家系成员的外周血标本,选取下颌前突家系中部分患者进行染色体核型分析；提取全血基因组DNA,采用Infinium HumanLinkage-12Beadchip基因芯片通过全基因组扫描和连锁分析方法进行下颌前突致病基因定位；在定位下颌前突致病基因区间的基础上,采用传统测序技术进行候选基因的突变检测,以期克隆下颌前突家系的致病基因。结果该下颌前突家系的遗传模式为常染色体显性遗传伴外显不全；家系患者的临床特征为下颌前突,侧貌凹面型,磨牙近中关系,前牙反(?),骨性Ⅲ类错(?)；染色体核型分析,在550-850条带阶段未见该下颌前突家系患者有染色体异常；全基因组扫描和连锁分析显示该下颌前突家系在2q14.3—2q22.1区间显著连锁；在17q24.2-17q25.1区间可能连锁；测序分析未能在ACVR2A基因中发现与该下颌前突家系有关的突变。结论1、该下颌前突家系患者临床特征为上颌正常、下颌前突,侧貌为凹面型,磨牙近中关系,前牙反(?),骨性Ⅲ类错(?)。2、该下颌前突家系遗传模式为常染色体显性遗传伴外显不全。3、通过染色体核型分析,排除该下颌前突家系由染色体异常导致。4、通过全基因组扫描和连锁分析,将该下颌前突家系致病基因定位到2q14.3-2q22.1区域,这是一个新的下颌前突致病基因位点。同时,17q24.2-17q25.1区间也与该下颌前突家系存在连锁的可能。通过测序分析,我们未能在ACVR2A基因中发现与该下颌前突家系有关的突变。更多还原

【Abstract】 Purpose:Mandibular prognathism is a common clinical problem with a substantial genetic component, but few susceptibility loci have been mapped. To investigate the etiology in a large autosomal-dominant inherited mandibular prognathism pedigree from China Tu-jia nationality.Methods:A large pedigree from China Tu-jia nationality was recruited. Family history material was collected using a detailed questionnaire. After detailed clinical evaluation, clinical photographs, panoramic and lateral cephalometric radiographs were performed on all the available family members. Family tree was drawn and the heritability model was determined. The peripheral blood of proband and other available individuals was obtained after achieving informed consent. Karyotyping analysis was performed in the part of family members. We analyzed the pedigree with6,090genome-wide single-nucleotide polymorphism (SNP) markers from Infinium HumanLinkage-12Beadchip (Illumina, San Diego, USA). Multipoint parametric linkage analyses were performed with MERLIN1.1.2for this pedigree. To find out the novel predisposing gene, candidate genes were resequencing using ABI3130sequence analyzer.Results:Autosomal dominant inheritance was determined according to the family tree. The family clinical feature was mandibular prognathism with normal maxillary, cancave profile, medial moral relationship, anterior crossbite and skeletal Class III malocclusion. There was no any chromosome abnormality found at the550-850band level. Linkage analysis identified a LOD score>3with the markers on chromosome2q14.3—2q22.1. ACVR2A, which encodes activin A type Ⅱ receptor, was resequenced as a candidate gene and no causal variation was identified.Conclusions:1、The clinical feature in this family was mandibular prognathism with normal maxillary, cancave profile, medial moral relationship, anterior crossbite and skeletal Class III malocclusion.2、The inheritance model in this family was autosomal dominant inheritance with incomplete penetrance.3、Chromosome abnormality was not the causal genetic variation in this family.4、A new genomic region,2q14.3—2q22.1, was identified linkage with the trait in the family. Another region,17q24.2-17q25.1, was also a candidate position. This linkage region provides target for susceptibility gene identification. Sanger resequencing did not find any causal variation in ACVR2A gene.更多还原